7WGQ

X-ray structure of human PPAR gamma ligand binding domain-pemafibrate co-crystals obtained by co-crystallization

7WGQ の概要

• エントリーDOI: 10.2210/pdb7wgq/pdb
• 分子名称: Isoform 1 of Peroxisome proliferator-activated receptor gamma, 15-meric peptide from Nuclear receptor coactivator 1, (2~{R})-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoic acid, ... (4 entities in total)
• 機能のキーワード: nuclear receptor, protein-ligand complex, ppar, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34201.72

構造登録者

Kamata, S.,Honda, A.,Akahane, M.,Machida, Y.,Uchii, K.,Shiiyama, Y.,Masuda, R.,Oyama, T.,Ishii, I. (登録日: 2021-12-28, 公開日: 2022-05-25, 最終更新日: 2023-11-29)

主引用文献

Honda, A.,Kamata, S.,Akahane, M.,Machida, Y.,Uchii, K.,Shiiyama, Y.,Habu, Y.,Miyawaki, S.,Kaneko, C.,Oyama, T.,Ishii, I.
Functional and Structural Insights into Human PPAR alpha / delta / gamma Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays-a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ-bezafibrate, PPARγ-fenofibric acid, and PPARδ/γ-pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.

PubMed: 35563117
DOI: 10.3390/ijms23094726

実験手法

X-RAY DIFFRACTION (2.43 Å)